既往研究发现实验药物AMPI-109能够有力杀灭三阴性乳腺癌细胞，但是培养皿中再有力的证据也不足以推动药物进入人体临床试验，即使是对三阴性乳腺癌这种致死率非常高并且目前很大程度上仍无靶向疗法选择的疾病。
2016年8月15日，英国《自然》旗下《肿瘤发生》在线发表美国科罗拉多大学的研究报告，发现AMPI-109通过反转肝再生磷酸酶3（PRL-3）的开关而发挥作用，抑制这种分子的活性可使三阴性乳腺癌细胞进入休眠或衰老，随后导致细胞死亡。
已知细胞内的肿瘤坏死因子受体1（TNF-R1）信号通路，既可以帮助细胞存活，也可以导致细胞死亡。但是，导致该通路促进存活或促进死亡的信号调节却知之甚少，特别是在癌细胞中。该研究在三阴性乳腺癌细胞中观察到PRL-3可能是上述过程的一个调节因子。当该基因被激活可使细胞存活，而当其失活可使细胞衰老并最终死亡。
在环境较好的时候，PRL-3能够启动某些基因的表达，招引免疫系统的某些成分促进癌症生长，而当环境比较恶劣的时候，癌细胞就会进入休眠。该研究利用基因技术将三阴性乳腺癌PRL-3表达降低，同时用药物AMPI-109通过阻断PRL-3发挥类似作用，使细胞发生衰老和凋亡，发现AMPI-109的作用效果与之非常类似，表明AMPI-109能够使细胞进入衰老，并且之后会让癌细胞度过该阶段进入凋亡程序。
如今，免疫疗法正逐渐成为多种癌症一线治疗选择。简而言之，这种策略能够教会免疫系统识别并攻击肿瘤组织，但是某些癌症比较善于躲避免疫系统的攻击，因此许多免疫疗法都只能将癌症的发展维持在比较低的水平而无法完全清除。事实上某些免疫疗法也将癌症作为一种慢性疾病进行治疗，通过持续治疗无限期地遏制癌症发展。
该研究提出，通过类似AMPI-109的药物抑制PRL-3活性，可以向免疫系统发送信号对肿瘤进行定位，还可以增加肿瘤对免疫治疗的敏感性，从本质上提高肿瘤的免疫治疗效果。如果进一步研究结果仍然明确支持该研究结论，AMPI-109将有可能成为借助免疫疗法靶向治疗三阴性乳腺癌的有力工具。
Oncogenesis. 2016 Aug 15;5(8):e255.
Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth.
Gari HH, DeGala GD, Lucia MS, Lambert JR.
University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-κB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-κB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-κB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-κB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival-death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival-death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner.
PMID: 27526109
DOI: 10.1038/oncsis.2016.50
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